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Statins and cancer

Clinical bottom line

Large randomised controlled trials of monotherapy for five years show no evidence of changes in the overall rates of fatal or non-fatal cancer, or in site-specific cancers with statin use.


Background

A number of epidemiological studies have reported an association between low cholesterol levels and increased incidence of cancer of the gastrointestinal tract. Most of the studies predate the introduction of statins in 1987, and when the lipid-lowering potential of these drugs was realised there were fears that they could increase the incidence of gastrointestinal cancers. However, causality remains controversial, and the association could be explained by confounding factors.

Under experimental conditions, statins have been shown to increase the frequency of several cancers in rodents, at levels of exposure similar to that used therapeutically in humans [1]. Recent in vitro studies demonstrate that statins can act as immunoregulators, and it is suggested that they could contribute to the development of malignant diseases by this mechanism [2, 3].

At the same time, other studies have suggested that statins have an inhibitory effect on cancer cell proliferation in vitro [4, 5], in an animal model [5] and in humans, when used for adjuvant treatment [6]. They may act as triggers of tumor-specific apoptosis [7].

Two recent case control studies, involving over 10,000 individuals, have looked for changes in the rates of cancer at specific sites, but failed to demonstrate a clear association with statin use [8, 9].

Review evidence

The strongest evidence, in terms of methodological rigor, number of patients and duration of follow-up, comes from large, randomised, double-blind, placebo-controlled trials. A meta-analysis of five trials studied 30,817 patients treated for 5 years, and found no association between the use of statins and either fatal or non-fatal cancers [10].

Bandolier has added to the meta-analysis the results of another very large trial published subsequently [11]. Not one trial reported all of the outcomes, and most reported cancer in different ways.

Table 1. Risk of fatal and non-fatal cancer with statin therapy

Event

Number of trials (refs)

Number of patients

Statin events/total

Placebo events/total

Relative risk (95% CI)

Non-fatal cancer
excluding nonmelanoma skin cancer

3 (1)

31575

583/15792

576/15783

1.01 (0.90-1.13)

including nonmelanoma skin cancer

2 (2)

13173

374/6593

374/6580

1.00 (0.87-1.15)

Fatal cancer
excluding nonmelanoma skin cancer

3 (1)

31575

436/15792

429/15783

1.02 (0.89-1.16)

including nonmelanoma skin cancer

2 (2)

13173

177/6593

186/6580

0.95 (0.78-1.16)

All cancers
excluding nonmelanoma skin cancer

4 (3)

38198

1271/19114

1264/19084

1.00 (0.93-1.08)

including nonmelanoma skin cancer

4 (4)

40314

2110/20166

2067/20148

1.02 (0.96-1.08)

1 SSSS, WOSCOPS, HPS
2 CARE, LIPID
3 SSSS, WOSCOPS, AFCAPS, HPS
4 CARE, LIPID, AFCAPS, HPS

Looking at all cancers together might obscure a change in the rate of a specific type or site of cancer. Reporting of site-specific cancers in the trials was incomplete, but the available data showed little evidence that statins influence cancer rates at specific sites.

Comment

So far the data from large randomized trials is mostly reassuring, although incomplete. The average duration of the trials was 5 years, but most patients taking stains would expect to do so for life. Cancers can occur after long latency periods following exposure to the carcinogen, and we do not yet have the length of follow-up necessary to exclude a carcinogenic effect of statins. The answer will come from epidemiological surveillance and studies with long-term follow-up.

References

  1. TB Newman, SB Hulley. Carcinogenicity of lipid-lowering drugs. JAMA 1996 275: 55-60.
  2. B Kwak et al. Statins as a newly recognized type of immunomodulator. Nat Med 2000 6: 1399-402.
  3. G Weitz-Schmidt et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 2001 7: 687-92.
  4. T Kusama et al. Inhibition of epidermal growth factor-induced RhoA translocation and invasion of human pancreatic cancer cells by 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors. Cancer Res 2001 61: 4885-91.
  5. T Kusama et al. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis.
  6. S Kawata et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer 2001 84: 886-91.
  7. WW Wong et al. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia 2002 16: 508-19.
  8. L Blais et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study. Arch Intern Med 2000 160: 2363-8.
  9. PF Coogan et al. Statin use and the risk of breast and prostate cancer. Epidemiology 2002 13: 262-7.
  10. LM Bjerre, J LeLorier. Do statins cause cancer? A meta-analysis of large randomized clinical trials. Am J Med 2001 110: 716-23.
  11. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002 360:7-22.